COMMON MINIMUM TECHNICAL STANDARDS AND PROTOCOLS FOR BIOBANKS DEDICATED TO CANCER RESEARCH
MAIMUNA MENDY, ELODIE CABOUX, RITA T. LAWLOR, JESSICA WRIGHT, AND CHRISTOPHER P. WILD
IARC TECHNICAL PUBLICATION NO. 44 COMMON MINIMUM TECHNICAL STANDARDS AND PROTOCOLS FOR BIOBANKS DEDICATED TO CANCER RESEARCH
MAIMUNA MENDY, ELODIE CABOUX, RITA T. LAWLOR, JESSICA WRIGHT, AND CHRISTOPHER P. WILD
IARC TECHNICAL PUBLICATION NO. 44 Published by the International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France
©International Agency for Research on Cancer, 2017
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Cover image: Paraffin-embedded tissues processed and stored within the context of various IARC research projects (Credit: R. Dray/IARC).
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IARC Library Cataloguing in Publication Data
Common minimum technical standards and protocols for biobanks dedicated to cancer research / Maimuna Mendy, Elodie Caboux, Rita T. Lawlor… [et al.]
(IARC Technical Publications; 44)
1. Biological Specimen Banks – Standards 2. Biological Specimen Banks – Organization & Administration 3. Biological Specimen Banks – Methods 4. Neoplasms I. Mendy, M. II. Title III. Series
ISBN 978-92-832-2463-1 (NLM Classification: W1) ISSN 1012-7348 Table of contents
Contributors ...... iv Acknowledgements ...... v Foreword ...... vi Preamble ...... vii Abbreviations ...... ix
Section 1 ...... 1 Glossary and definitions
Section 2 ...... 5 Role of biobanks in cancer research
Section 3 ...... 11 Recommendations for biobanks
Section 4 ...... 55 Selected protocols
References ...... 63
Annex 1 ...... 69 IARC policy on access to human biological materials
Annex 2 ...... 75 Guidelines for informed consent
Annex 3 ...... 80 Template consent form for biobanking
Annex 4 ...... 91 Template Material/Data Transfer Agreement (MTA/DTA)
Annex 5 ...... 97 Biobank, collection, study, and sample minimum data set and associated standards
Disclosures of interests ...... 101 Contributors
Authors Dr Joakim Dillner Dr Ghislaine Scélo Karolinska Institutet Genetic Epidemiology Group, Dr Maimuna Mendy Stockholm, Sweden Section of Genetics Head, Laboratory Services and International Agency for Research Ms Marianne Henderson Biobank Group on Cancer (IARC) Senior Advisor for Division International Agency for Research Lyon, France Resources, Office of the Director, on Cancer (IARC) Division of Cancer Epidemiology Ms Anne-Marie Tassé Lyon, France and Genetics Executive Director, Dr Elodie Caboux Senior Advisor on Biobanking, Public Population Project in Laboratory Services and Center for Global Health, National Genomics and Society (P3G) Biobank Group Cancer Institute, National Institutes Montreal, Canada International Agency for Research of Health, Division of Health and Dr Jim Vaught on Cancer (IARC) Human Services President, International Society Lyon, France Rockville, MD, USA for Biological and Environmental Dr Rita T. Lawlor Dr Jan-Eric Litton Repositories (ISBER) ARC-NET Centre for Applied Director General, Biobanking and Editor in Chief, Biopreservation Research on Cancer BioMolecular resources Research and Biobanking University of Verona Infrastructure–European Research Senior Research Fellow, Verona, Italy Infrastructure Consortium (BBMRI- International Prevention Research ERIC) Institute, Lyon, France Dr Jessica Wright Graz, Austria Study Manager, Sheffield Clinical Dr Kurt Zatloukal Trials Research Unit Dr Manuel Morente Deputy Head, Institute of Pathology The University of Sheffield Biobank Scientific Director, Spanish Medical University of Graz Sheffield, United Kingdom National Cancer Research Centre Graz, Austria (CNIO) Mr Ma’n H. Zawati Dr Christopher P. Wild Coordinator, Spanish National Executive Director, Centre of Director, International Agency for Biobank Network Genomics and Policy Research on Cancer (IARC) Past-President, European, Middle McGill University Lyon, France Eastern and African Society for Montreal, Canada Biopreservation and Biobanking (ESBB) Reviewers Madrid, Spain Production Team The authors are grateful to the Dr Sabina Rinaldi following expert colleagues who Biomarkers Group, Section of Karen Müller English Editor contributed comments, advice, Nutrition and Metabolism corrections, and protocols in the International Agency for Research Sylvia Lesage preparation of this book. on Cancer (IARC) Publishing Assistant Lyon, France
iv Contributors Acknowledgements
We would like to acknowledge the authors of Common Minimum Technical Standards and Protocols for Biological Resource Centres Dedicated to Cancer Research (published by IARC in 2007): an IARC Secretariat composed of Dr Elodie Caboux, Dr Amelie Plymoth, and Dr Pierre Hainaut, joined by the Working Group participants.
The authors would like to thank Ms Sally Moldan, for her excellent contribution towards the compilation of this book, and the members and partners of the Low- and Middle-Income Countries (LMICs) Biobank and Cohort Building Network (BCNet), for sharing their real-life experiences working in resource-constrained settings.
Acknowledgements v Foreword
Biological specimens collected, from the International Agency for what goes into a biobank but also on processed, and stored under opti- Research on Cancer (IARC). The what comes out. There is a risk that mal conditions increasingly provide purpose of the text is to provide biobanks remain untouched or un- a necessary foundation for cancer clear and practical advice on the derexploited, a deposit that is rarely research. Information obtained from common practices needed to create put to work for the common good. such samples opens opportunities and maintain biobanks, recognizing While this book aims to ensure that to learn more about the causes, that the circumstances faced by the what goes into a biobank is of high prevention, and treatment of the curators of biobanks vary across quality and well managed, it has as disease. International comparisons the world. The international coop- its ultimate objective to drive the use made possible by the study of sam- eration that went into formulating of those same biospecimens in re- ple collections from different parts of these Common Minimal Technical search. This will involve the analysis the world are also invaluable in the Standards provides confidence that of biospecimens, but to maximize the pursuit of the evidence base for can- the content is realistic, while at the benefits it will also require linkage to cer control. same time maintaining the minimal other well-documented epidemio- However, the above-mentioned standards needed in order for the logical and clinical data sets. In this opportunities are accompanied by biospecimens to be valid and to period of spiralling numbers of can- many challenges and potential pit- yield the reliable research data be- cer cases and costs of cancer care, falls. At times, pragmatic decisions ing sought. In providing this Fore- the failure to use stored samples to have to be made in response to the word, I would like to place on record answer critical research questions is constraints faced when conducting my thanks to all authors and review- indefensible. clinical or population-based studies. ers who have contributed to this final In conclusion, I trust that readers These constraints may be techni- product, as well as to all the contrib- will find this publication to be a sup- cal, may relate to infrastructure or utors to Common Minimum Techni- port to successful biobanking and finance, or may be ethical, legal, cal Standards and Protocols for Bio- will find herein one important foun- or social in nature. Being unaware logical Resource Centres Dedicated dation for cancer research in the of these types of risk to successful to Cancer Research, known as the 21st century. biobanking can place important sci- “Green Book”, published by IARC in entific advances in jeopardy. 2007. Dr Christopher P. Wild In this context, it is a great plea- In publishing this book, my hope Director, International Agency sure to introduce this publication is for a balanced focus, not only on for Research on Cancer
vi Foreword Preamble
The International Agency for In response to these develop- (LMICs). The recommendations are Research on Cancer (IARC) pub- mental changes and to promote col- based on validated and/or evidence- lished Common Minimum Technical laborative projects, a wide range of based guidelines, taking into account Standards and Protocols for Biologi- biobanking stakeholders are estab- the current knowledge of biobanking cal Resources Centres Dedicated lishing approaches and mechanisms practices and standards resulting to Cancer Research, known as the for the harmonization of resources, from projects such as Standardisa- “Green Book”, in 2007. The recom- including data. These stakehold- tion and Improvement of Generic Pre- mendations and protocols in that ers include international organiza- analytical Tools and Procedures for In publication were largely based on tions, societies, and institutions, Vitro Diagnostics (SPIDIA), BBMRI– guidelines, procedures, and docu- such as the United States National Large Prospective Cohorts (BBMRI- mentation on biorepositories devel- Cancer Institute (NCI), the Interna- LPC), and the International Geno- oped by several working groups, tional Society for Biological and En- mics Consortium (IGC), as well as the institutions, regulatory bodies, and vironmental Repositories (ISBER), European Committee for Standard- organizations, including the World the European, Middle Eastern and ization (CEN) Technical Specifica- Health Organization. African Society for Biopreserva- tions for molecular in vitro diagnostic However, biobanking has devel- tion and Biobanking (ESBB), and examinations and International Or- oped at a rapid pace over the years, the Biobanking and BioMolecular ganization for Standardization (ISO) driven mainly by the push for person- resources Research Infrastructure– norm 15189 (ISO, 2012). ISO 15189 is alized medicine, the need for high- European Research Infrastructure currently under revision (https://www. quality biological resources and as- Consortium (BBMRI-ERIC). Their iso.org/obp/ui/#iso:std:iso:15189:ed- sociated data for scientific research, activities include the improvement of 3:v2:en), and the working groups and technological advancement of biobanking protocols and standards of the Technical Committee of ISO analytical platforms for molecular to provide high-quality samples and 276 (http://www.iso.org/iso/home/ and genetic research. These devel- to adequately address ethical, legal, standards_development/list_of_iso_ opments have enabled the collec- and social issues (ELSI). technical_committees/iso_technical_ tion and analysis of large numbers This IARC Technical Publica- committee.htm?commid=4514241) of biospecimens in combination with tion includes guidelines and recom- are dealing with biobanking qual- epidemiological and clinical data mendations for biobanks not only in ity issues, including terminology, collected across populations and in- high-income countries but also in bioresearch, bioprocessing, pre- volving multiple biobanks. low- and middle-income countries analytical methods, isolation of
Preamble vii analytes, and data processing and fective running of the facilities. Tem- The guidelines and recommen- integration. plates for informed consent and Ma- dations are applicable to biobanks This book also includes sections terial and Data Transfer Agreements operating in different geographical on sample sharing, ELSI, and harmo- are available in the Annexes section. locations, and although the book’s nization guidelines important to sup- This new book also benefits focus is on biobanks dedicated to port collaborative research efforts from the experience and knowl- cancer research, the principles and that make use of biological materi- edge gained by IARC from coordi- guidelines outlined here are also als. In particular, the section on open nating the LMICs Biobank and Co- applicable to non-cancer biobanks. access deals with the principles of hort Building Network (BCNet) and Table 1 presents a list of the sharing and provides recommenda- managing an international biobank, main sources of information used tions for biobanks in relation to sam- which contains diverse collections to develop the recommendations ple and data sharing, which is key to of specimens and data drawn from presented in this book. Whenever establishing research collaboration. studies across the world, including appropriate, the book indicates ref- The section on governance provides the European Prospective Inves- erences and links to more extensive guidelines on governance structures tigation into Cancer and Nutrition documentation and protocols. for biobanks for transparent and ef- (EPIC) collection.
Table 1. Guidelines, procedures, and documentation on biobanks
Title Authors/origin
Tissue banking for biomedical research National Cancer Centre Singapore
Biorepository protocols Australasian Biospecimen Network (ABN)/Australia
Standardizing tissue collection and quality control procedures for a European Human Frozen Tumour Tissue Bank (TuBaFrost) European virtual frozen tissue bank network Human tissue and biological samples for use in research: operational Medical Research Council (MRC)/United Kingdom and ethical guidelines 2012 Best practices for repositories: collection, storage, retrieval, and International Society for Biological and Environmental Repositories distribution of biological materials for research (ISBER)/International NCI best practices for biospecimen resources National Cancer Institute (NCI)/USA
Guidance on regulations for the transport of infectious substances World Health Organization (WHO)/International United Nations recommendations on the transport of dangerous goods, United Nations Economic Commission for Europe (UNECE)/ model regulations, 19th revised edition International Recommendation Rec(2006)4 of the Committee of Ministers to Member Council of Europe Committee of Ministers States on research on biological materials of human origin Collection, transport, preparation, and storage of specimens for Clinical and Laboratory Standards Institute (CLSI)/USA molecular methods: approved guideline The Human Proteome Organization Human Proteome Organization (HUPO)
Case studies of existing human tissue repositories: “best practices” for RAND Corporation/USA a biospecimen resource for the genomic and proteomic era Biological resource centres: underpinning the future of life sciences and Organisation for Economic Co-operation and Development (OECD)/ biotechnology International OECD best practice guidelines for biological resource centres Organisation for Economic Co-operation and Development (OECD)/ International Standard operating procedure for the collection of fresh frozen tissue European Organisation for Research and Treatment of Cancer samples (EORTC)
viii Abbreviations
ACD acid citrate dextrose BBMRI-ERIC Biobanking and BioMolecular resources Research Infrastructure–European Research Infrastructure Consortium BBMRI-LPC BBMRI–Large Prospective Cohorts BCNet LMICs Biobank and Cohort Building Network BRIF Bioresource Research Impact Factor BRISQ Biospecimen Reporting for Improved Study Quality CEN European Committee for Standardization
CO2 carbon dioxide CSF cerebrospinal fluid DBS dried blood spot DEPC diethylpyrocarbonate DIN DNA integrity number DMSO dimethyl sulfoxide DNA deoxyribonucleic acid DR disaster recovery dsDNA double-stranded DNA DTA Data Transfer Agreement EDTA ethylenediaminetetraacetic acid ELSI ethical, legal, and social issues EPIC European Prospective Investigation into Cancer and Nutrition ESBB European, Middle Eastern and African Society for Biopreservation and Biobanking EU European Union FBS fetal bovine serum FFPE formalin-fixed, paraffin-embedded GA4GH Global Alliance for Genomics and Health gDNA genomic DNA HBV hepatitis B virus HIV human immunodeficiency virus IARC International Agency for Research on Cancer IATA International Air Transport Association ICAO International Civil Aviation Organization
Abbreviations ix ISBER International Society for Biological and Environmental Repositories ISO International Organization for Standardization IT information technology LIMS laboratory information management system LMICs low- and middle-income countries
LN2 liquid nitrogen MIABIS Minimum Information about Biobank Data Sharing miRNA microRNA MTA Material Transfer Agreement NCI United States National Cancer Institute NIH United States National Institutes of Health OCT optimal cutting temperature OECD Organisation for Economic Co-operation and Development P3G Public Population Project in Genomics and Society PCR polymerase chain reaction QA quality assurance QC quality control QMS quality management system qPCR quantitative PCR R&D research and development RIN RNA integrity number RNA ribonucleic acid rRNA ribosomal RNA RT-PCR reverse transcription PCR SOPs standard operating procedures SPREC Sample PREanalytical Code ssDNA single-stranded DNA TNM tumour–node–metastasis TuBaFrost European Human Frozen Tumour Tissue Bank UNECE United Nations Economic Commission for Europe UV ultraviolet WHO World Health Organization
x SECTION 1 SECTION
section 1. Glossary and definitions
Unless otherwise defined in an- Aliquot usually detected by staff of the area other context in this book, important Aliquoting is a process in which a in which the event occurred, which terms are defined below. specimen is divided into separate may result in non-compliance with Some of the definitions are ac- parts, which are typically stored as the quality management system or cording to the 2012 International So- individual samples. The term “ali- with the requirements of the user. ciety for Biological and Environmen- quot” may also be used as a noun tal Repositories (ISBER) guidelines to denote a single sample. It is ad- Anonymization (ISBER, 2012). visable to store aliquots in separate The process in which identifying It should be noted that the Inter- containers, to minimize loss due to information or details are re- national Organization for Standard- unexpected equipment failure. moved from the data collected with ization (ISO) standards that are cur- a sample, so that the sample donor rently under development and will be Analyte remains anonymous. released within 2 years (ISO/TC 276 A substance or chemical constituent Biotechnology) will include a section that is determined in an analytical Associated data on biobanking definitions. procedure. The clinical, pathological, and epide- miological information related to pa- Adverse event Annotation tients who provided a sample. The Any event that caused harm or had Additional information associated information relates to characteristics the potential to cause harm to any with a particular point in a document of the sample, the study participant, biobank personnel or visitors, in- or other piece of information. and biological experiments that can cluding but not limited to breach of be used to generate knowledge. security of the premises and its con- Anomaly tents, or harm to biospecimens or An unexpected event occurring with- Autopsy data integrity or linkage. in the quality management system, The postmortem examination of
Section 1. Glossary and definitions 1 organs and tissues of a body, to de- that can affect human health. It can Container termine cause of death or pathologi- also include substances harmful to An enclosure for one or more units cal conditions. animals. of a specimen or specimens.
Biobank Biological resource Controlled areas Infrastructure for the collection, ar- A collection of biological specimens Restricted work areas of low micro- chiving, and storage of biospeci- and associated data that are ac- bial and particulate content in which mens and their associated data, and quired for a defined purpose. The non-sterile materials are prepared. the procedures and related servic- custodian of the collection is re- es connected to the biospecimens sponsible for the management of the Custodian and associated data. The services biological resource. Biological re- The person responsible for the include informing individuals who sources may be stored in a biobank management of a biological re- are approached to participate in a or laboratory and in databases, de- source. The custodian works with study, obtaining their consent, col- pending on the number of samples, other key stakeholders in the man- lecting and processing specimens the volume of information, and the agement of the resource, including for secure long-term storage, ac- governance structure of the biobank. the tracking of all relevant documen- cessing and retrieving specimens tation for the resource, and is re- appropriate for analysis, processing Biological safety hood sponsible for ensuring that policies for preparation of biomaterials (e.g. A cabinet designed to provide a mi- on access to the resource are in DNA, RNA, proteins), quality con- crobe-free work environment, which place and are implemented accord- trol, and packaging and shipping of enables work on samples in an ing to appropriate guidelines. specimens. Many types of biobank isolated area. are relevant to cancer research. Database They include, among others, tumour Biorepository A structured collection of records and tissue biobanks for specimens See “Biobank”. or data that is stored in a computer and data obtained in the course of system so that a computer program normal clinical procedures; special- Coding or a person using a query language ized collections of specimens and Substituting a code for personally can consult it to answer queries. data developed in the context of identifying information in such a way clinical trials, mechanistic studies, that linkage is only possible through Dehydration or diagnostic or prognostic studies; a key. The removal of water from a tissue. and collections of specimens and data developed in epidemiologi- Cold chain De-identification cal studies and biomarker studies. A temperature-controlled supply chain. A process that ensures that a per- Biobank samples include tissues, son’s identity cannot be connected blood, cell lines, DNA, and pro- Cold ischaemia with information or samples donated teins derived from individuals with a The condition of a tissue sample af- by them. history of hereditary or familial ter its removal from the body until its cancer. Biobanks are also known as stabilization or fixation. Desiccant biorepositories. A desiccant is a hygroscopic sub- Collection stance that induces or sustains a Biobanking The practice or technique of collect- state of dryness (desiccation) in its The process of storing material or ing a specimen, or a specific sam- vicinity. Commonly encountered specimens and associated data for ple or group of samples, that has pre-packaged desiccants are solids future use. been isolated for future research that absorb water. purposes. Biohazard Deviation An organism, or a substance de- Consignee An intentional or unintentional event rived from an organism, that poses Any individual, agency, institution, that departs from a set procedure or a threat to (primarily) human health. or organization that receives speci- normal practice. This can include medical waste and mens and assumes responsibility for samples of a microorganism, virus, storing, dispensing, and tracking the Dewar or toxin (from a biological source) disposition of specimens. A specialized container that holds
2 liquefied gases. A dewar may also Incident at −196 °C. Samples stored in the be referred to as a dewar flask or Any unplanned occurrence that vapour phase of liquid nitrogen are dewar vessel, or a liquid nitrogen deviates from standard operating −190 °C and warmer, depending on tank. procedures (SOPs) or applicable the distance from the liquid phase. government laws and regulations 1 SECTION Distribution during specimen retrieval, process- Liquid nitrogen tank A process that includes receipt of ing, labelling, storage, or distribution See “Dewar”. a request for specimens, selection that may affect subsequent use of of appropriate specimens, and those specimens. Lyophilized final inspection, in conjunction with Dehydrated for storage by conver- subsequent shipment and delivery Individual sion of the water content of a frozen of specimens to another biobank, The person who is the subject of pro- specimen to a gaseous state under specimen collection centre, or tected health information. vacuum. Also called “freeze-dried”. laboratory. Informed consent Material Transfer Agreement (MTA)/ Donor A decision to participate in research, Data Transfer Agreement (DTA) A person who donates or gives an taken by a competent individual An agreement or contract that gov- organ, blood, or blood products to who has received the necessary in- erns the transfer of research materi- another person. formation; who has adequately un- als and/or data between two organi- derstood the information; and who, zations, when the recipient intends to Dry ice after considering the information, use them for research purposes. It
Solid-phase carbon dioxide (CO2). has arrived at a decision without defines the rights and obligations of
CO2 solidifies at −78.5 °C. having been subjected to coercion, the provider and the recipient with undue influence, inducement, or respect to the use of the materials End user intimidation. and/or data. A health-care practitioner, scien- tist, or laboratory staff member who Institution Monitoring system performs an appropriate procedure, The body responsible for speci- A system that monitors the temper- test, or archival function. men collection and archiving that ature and environmental conditions, commits itself to the development, including alarms, in conjunction with Error management, and long-term main- remote access, security features, A deviation from a standard operat- tenance of a biobank. Although the and electronic data storage. ing procedure (SOP) during speci- organizational nature of such insti- men retrieval, processing, testing, tutions may vary widely, they are Participant quarantining, labelling, storage, or primarily clinical cancer centres, A person who takes part in a trial. distribution that might adversely academic medical centres, research Participants must usually meet cer- affect the specimen. institutes closely associated with tain eligibility criteria. clinical centres, or central organiza- Ethical, legal, and social issues tions dedicated to the management Patient (ELSI) of biobanks. A person who receives medical at- The ethical, legal, and social issues tention, care, or treatment. associated with the development Institutional review board (IRB) and operation of a biobank. See “Research ethics committee Pre-analytical data (REC)”. Factors that may have an impact on Identifier the integrity of the sample during the Information (e.g. name, social se- Label collection, processing, and storage curity number, medical record Any written, printed, or graphic mate- processes. These data include infor- number, or pathology accession rial on or affixed to a specimen con- mation on the treatment of the sam- number) that would enable the iden- tainer or package. ple, including the conditions and the tification of the subject. For some duration of the treatment. specimens, this information might Liquid nitrogen (LN2) include the taxon name and the Coolant used to cool and store Preservation collection number. samples. Nitrogen becomes liquid The use of chemical agents, alterations
Section 1. Glossary and definitions 3 in environmental conditions, or oth- Re-identification Snap-freezing er means during processing and A reversible process that allows The process by which the temper- storage to prevent or retard bio- data from which identifiers have ature of samples is lowered very rap- logical or physical deterioration of a been removed, and replaced by idly to below −70 °C using dry ice or specimen. a code, to be re-identified and liquid nitrogen. linked to a specific individual by, for Procedure example, using the code or linking Specimen A series of steps that, when followed different data sets. A specific tissue sample, blood sam- in order, are designed to result in a ple, and so on taken from a single specific outcome. Removal subject or donor at a specific time. See “Retrieval”. Processing Standard operating procedures Any procedure used after specimen Repository (SOPs) collection but before distribution, An entity that receives, stores, pro- A set of detailed written instructions including preparation, testing, and cesses, and/or disseminates speci- to achieve uniformity of the perfor- releasing the specimen to inventory mens, as needed. This term encom- mance of a specific function. and labelling. passes the physical location as well as the full range of activities associ- Storage Pseudo-anonymization ated with its operation. A repository Maintenance of specimens under The process whereby identifiable may also be referred to as a bio- specified conditions for future use. personal information is anonymized, repository or a biobank. but in such a way that the per- Subject sonal identifiers are replaced by one Research ethics committee (REC) A living or deceased individual who pseudonym, which can be linked A board, committee, or other group is the source of the specimen in ac- across multiple data records without formally designated by an institution cordance with established medical revealing the identity of the person. to review the ethical, legal, social, criteria, procedures, and privacy reg- scientific, and financial implications ulations. In some countries, the term Quality of biomedical research involving “Donor” or “Individual” may be used Conformance of a specimen or pro- humans as subjects, to approve in the same context as “Subject”, cess with pre-established specifica- the initiation of the research, and to especially in the context of human tions or standards. conduct periodic reviews of such re- specimens. search. In some countries, this body Quality assurance (QA) is known as an institutional review Traceability An integrated system of manage- board (IRB) or a research ethics The ability to locate a specimen dur- ment activities involving planning, board (REB). ing any step of its donation, collec- implementation, documentation, as- tion, processing, testing, storage, sessment, and improvement to Retrieval and disposition. ensure that a process or item is of The removal, acquisition, recov- the type and quality needed for the ery, harvesting, or collection of Warm ischaemia project. specimens. The condition in which the tissue is deprived of its normal blood Quality control (QC) Safety supply, containing oxygen and nu- The system of technical activities that Processes, procedures, and tech- trients, while the tissue is at body measures the attributes and perfor- nologies to ensure freedom from temperature. mances of a process or item against danger or harm. defined standards, to verify that the stated requirements are fully met. Sample A single unit containing material Quality management system (QMS) derived from one specimen. The organizational structure, pro- cedures, processes, and resourc- Shipping manifest es needed to implement quality A written description of the contents management. of a shipped package.
4 section 4. Selected protocols
4.1 Processing of blood DBS can be used for molecular biol- • Whatman Protein Saver Card (e.g. specimens ogy techniques and other diagnostic Whatman, 903; 10534612); assays. The cost and difficulty of cold • gas-impermeable storage bag (e.g. If serum and plasma samples are chain shipping of plasma samples are Fisher Scientific, NC9307519); being collected, the blood should greatly reduced by the use of DBS, • desiccant pack (e.g. Whatman, be centrifuged as soon as possible which can be shipped as non-dan- 10548234); after blood collection and separated gerous goods. • humidity indicator cards (e.g. Multi- immediately after centrifuging so that Always wear gloves when han- sorb Des Manufacture, MS200032); the samples can be frozen as soon as dling filter papers, and hold them • card drying rack (e.g. VWR, 89015- possible. This is critical for time-sen- only by the upper corner, marked 592) (optional; cards can be placed sitive samples for protein studies, for out for labelling. Do not allow the on a dry worktop if a drying rack is example. For the processing of blood card to come into contact with any not available); specimens, the following protocols unclean surface (e.g. bench, base of • gloves, preferably powder-free; and are recommended. hood). • sample label. The procedure should be per- 4.1.1 Filter paper dried blood formed in accordance with the relevant 4.1.1.1 Collection of DBS from spot collection, processing, health and safety practices specific finger prick storage, and shipment to specimen handling and waste dis- posal. A minimum level of training is i. Disinfect the selected site and Dried blood spot (DBS) is an easy required to perform the procedure. prick it using a lancet/needle. and inexpensive means of collection Reagents and materials required: ii. Uniformly saturate the entire circle and storage of peripheral blood spec- • finger prick device (e.g. Unistik 2 by quickly and gently touching, imens in settings where collection device; Fisher Scientific, 22-0227); not pressing, the puncture site to 4 SECTION and storage of plasma is not optimal. • alcohol swab; the filter paper.
Section 4. Selected protocols 55 iii. Note: Do not touch the Whatman 4.1.1.2 Preparation of DBS from DMSO is needed to keep them alive card at any stage of collection. EDTA, ACD, or heparin tubes while freezing. iv. After the collection of five blood i. Dispense 50 μL of DMSO into two spots, clean the site and leave it DBS can also be prepared from 1 mL sterile cryovials. unbandaged. EDTA, ACD, and heparin blood tubes. ii. Invert the EDTA tube twice, and v. Allow the blood spots to air-dry, i. Before starting, mix vacutainers then add 450 μL of blood to each without the flap covering the containing anticoagulated blood cryovial. spots, in a clean dry place that is by inversion. iii. Invert the cryovial to mix the protected from rodents or insects ii. Wipe the top of the vacutainer whole blood with the DMSO. and direct sunlight, for at least with 70% ethanol before opening Note: DMSO is cytotoxic at room 4 hours (overnight drying may the lid. temperature; therefore, as soon be needed in areas with higher iii. Using a micropipette, apply 40 µL as it is mixed with blood, it should humidity). of blood onto the circle on the be placed in a controlled-rate vi. Do not heat or stack DBS cards DBS card. freezer. or allow them to touch other iv. Air-dry the filter paper thoroughly iv. Transfer to −80 °C after at least surfaces during the drying pro- by following step v above (Sec- 4 hours. cess. tion 4.1.1.1), and continue with the vii. Tuck in the flap of the card as rest of the protocol as described 4.1.3 Plasma indicated on the card. above. viii. Clearly label the card with the pa- Plasma collected in EDTA or ACD tient identifier and date, or label it 4.1.1.3 Shipping of DBS cards tubes can be used for bioassays, with a prepared barcode label. plasma DNA isolation, proteomic ix. Be sure the DBS card is com- DBS are classified as “Exempt Bi- analysis, and biomarker discovery. pletely dry before packing. ological Specimens” according to i. Spin the vacutainer (about 9 mL) x. Insert the DBS card into a gas-im- the ICAO and IATA shipping regula- at 815g for 10 minutes at 4 °C to permeable plastic bag containing tions. DBS bags should be shipped separate plasma from blood cells. a desiccant pack and a humidity in courier envelopes or boxes under ii. After wiping each tube with indicator. Do not store more than ambient conditions according to 70% alcohol, remove about 3 mL one card per bag. the triple packaging system (see of plasma. (The tube can be xi. Ensure that the patient identifier Section 3.9.2). retained for white blood cell and date (or the prepared bar- i. Provide a shipping manifest for extraction.) code label) are on the outside of all boxes. The shipping manifests iii. Transfer to a labelled 15 mL tube, the bag as well as on the DBS must exactly match the label in- and centrifuge at 2500g for 10 card. formation and the order in the as- minutes at 4 °C. xii. Seal the plastic bag. sociated shipment, including the iv. Aliquot plasma into 1 mL labelled xiii. Place the sealed bag containing global specimen IDs. cryovials (three or four aliquots).
the DBS card in a clean, dry area ii. Provide a box map for all boxes. v. Place in LN2 dewar to snap- of the laboratory with no exposure The box maps must exactly match freeze.
to direct sunlight, free of insects the label information and the order vi. Store at −80 °C or in LN2. or rodents, and where ambient in the associated shipment, includ- The purpose of double-spinning temperatures will not exceed ing the global specimen IDs. the plasma is to remove all cellular 30 °C. iii. Record the courier service and contaminants so that the plasma is xiv. The room should be temperature- the courier air bill number on the suitable for plasma DNA analysis. and humidity-controlled (temper- specimen shipment notice. Therefore, it is extremely important ature of 20–22 °C and humidity of iv. Advance notification of shipment not to disturb the buffy coat after the not more than 22%). must be made to the recipient. first spin and any pellet after the sec- xv. Check the desiccant pack before ond spin. shipment of the DBS card and 4.1.2 Whole blood replace it if the colour of the hu- 4.1.4 Platelet-poor plasma midity indicator has changed from Whole blood is to be prepared from blue to pink or colourless. EDTA tubes. The anticoagulated Platelet-poor plasma can be used for xvi. Ship the DBS cards at ambient blood can be snap-frozen as it is. the isolation of plasma DNA (from temperature. If the blood cells are needed intact, EDTA tubes).
56 i. Spin blood at 3200g for 12 min- v. If division of the sample is nec- vii. Spin at 450g for 10 minutes. utes at room temperature. essary, at this point pour 25 mL viii. Pour off the supernatant into a ii. Pipette off plasma using a plas- of the sample into another centri- waste container containing chlo- tic Pasteur pipette. Transfer into fuge tube. rine bleach. Add 3 mL of cold a tube. vi. Spin both tubes at 1200g for 10 freezing mix (10% DMSO, 20% iii. Spin plasma at 2000g for 10 min- minutes. fetal calf serum [FCS], RPMI utes at 4 °C. vii. Repeat the washing if red blood 1640) and resuspend. iv. Aliquot into 1 mL aliquots in la- cells persist. ix. Dispense the white blood cells belled cryovials. viii. Carefully pour off the supernatant. into three 1 mL labelled cryovials v. Store at −80 °C. ix. Using a swirling motion, remove that have been sitting on ice. the pellet with a pipette and trans- x. Place on ice. Place vials in a 4.1.5 Buffy coat cells fer it to a labelled cryovial. controlled-rate freezer so as to
x. Store at −80 °C or in LN2 until cryopreserve cells under condi- The buffy coat is a thin, greyish-white further use. tions that maintain cell viability. layer of white blood cells (leukocytes As an alternative, red blood cells This should be done as soon as and lymphocytes) and platelets cov- can be lysed by using an ammoni- possible, because DMSO is toxic ering the top of the packed red blood um-containing lysis buffer. at room temperature. cells after centrifugation at 450g xi. Transfer on a weekly basis to LN2 (from EDTA- or ACD-containing 4.1.7 White blood cells tanks. blood tubes). Instead of a separation based on i. After having spun the blood, White blood cells collected in EDTA Ficoll, a Percoll separation can be take the buffy coat off with about or ACD tubes can be used for DNA used. 100 μL of plasma using a dispos- extraction and the creation of cell able sterile Pasteur pipette; be lines. 4.1.8 Serum careful not to lift red blood cells. i. Transfer the remaining blood ii. Lyse the remaining red blood cells from the plasma spin to a labelled The blood is collected into tubes by addition of red blood cell lysis 50 mL tube containing 10 mL of without addition of anticoagulants. buffer at room temperature. RPMI 1640. Then, two phases are distinguish- iii. Spin the tube at 450g for 10 min- ii. After swabbing the lid of this tube able: a solid phase containing fibrin utes at room temperature. with alcohol, aliquot 3 mL of Ficoll and cells, and a fluid phase contain- iv. Resuspend the pellet. into each of two clearly labelled ing the serum. v. Aliquot as appropriate into la- 15 mL tubes. This process should be complet- belled cryovials. iii. Carefully layer 9 mL of diluted ed after 30 minutes at room temper- vi. Place in LN2 to snap-freeze. blood onto each tube of Ficoll. ature, after which the process de- vii. Store in LN2. Treat gently, and do not mix, but scribed below should start. spin as soon as possible. i. Spin blood at 1500g for 10 min- 4.1.6 Blood pellets (white iv. Spin at 450g for 30 minutes. Note: utes at room temperature. blood cells) When centrifuging, do not use the ii. Aliquot 1 mL portions of the su- brake. pernatant into labelled cryovials.
Blood pellets can be used for the v. Remove most of the top layer iii. Place into LN2 dewar or dry ice to isolation of DNA (from EDTA or ACD (RPMI 1640) using a 1 mL Ep- snap-freeze. tubes). pendorf tip, and discard about iv. Transfer to −80 °C freezer or LN2. i. Transfer blood from the original 3–4 mL into a waste container tube to a labelled 50 mL tube. containing chlorine bleach. 4.2 Processing of solid tissue ii. Fill the tube with Tris-EDTA buff- vi. Collect white blood cells with the er (formula) and mix vigorously. same Eppendorf tip using a swirl- Careful and well-documented pro- Place on ice for 5–10 minutes. ing motion to “vacuum up” white cessing of tissue specimens is cru- iii. Spin at 1200g for 10 minutes. blood cells. Do not take too much cial to the overall usefulness of the iv. Carefully pour off the supernatant Ficoll (third layer), because it is biobank as a resource for scientific into a waste container containing toxic to the cells. Place the white research. Detailed records of the chlorine bleach. Briefly vortex blood cells into a labelled 15 mL first steps in the process of sample the pellet and add 50 mL of Tris- tube containing 10 mL of RPMI handling include the times of an- 4 SECTION EDTA buffer. Shake vigorously. 1640. aesthesia administration, ligation of
Section 4. Selected protocols 57 vessels, and specimen removal from freezing. All the different pre-analyt- 4.2.1.5 Role of the pathologist the patient. ical conditions and durations should These factors are important to be documented. i. Macroscopically describe the assess tissue quality, because they specimen as usual. affect the quality of the resulting bio- 4.2.1.1 Safety ii. Using clean instruments and on a molecules. The most commonly de- clean surface (sterile foil or clean scribed factor that has an impact on All procedures should be carried out dissection board), dissect the tis- tissue quality is the warm ischaemia in accordance with the local codes of sue specimen. Clean or change time, which is the period from when practice. Working with LN2 and iso- instruments between dissecting the blood supply is ligated until the pentane is hazardous; all procedures normal tissue and tumour tissue. specimen is placed in fixative in the must comply with local safety rules iii. Take representative parts of tis- pathology laboratory. Studies have specific to these chemicals. All tissue sue for routine diagnosis (for fixa- demonstrated that changes in both must be handled as if it is potentially tion and embedding) as a priority, RNA and protein occur during this infectious. and decide whether there is suf- time (Dash et al., 2002). ficient material available for the These protocols for collecting 4.2.1.2 Hospital ward tissue bank. and freezing tissue samples were a. Supply the research technician developed within the European Hu- Consent must be obtained from the with a tissue sample or sam- man Frozen Tumour Tissue Bank patient before surgery (if applicable, ples for biobanking representa- (TuBaFrost) project (Riegman et al., according to the law and procedures tive parts of the lesion, normal 2006b) and the Standardisation and in the country where the samples are tissue, and pre-malignant con- Improvement of Generic Pre-ana- being collected). ditions. lytical Tools and Procedures for In b. Perform QC of frozen tissue Vitro Diagnostics (SPIDIA) project 4.2.1.3 Operating theatre and annotation. (Malentacchi et al., 2015). These recommended protocols i. Deliver the notification of tissue 4.2.1.6 Role of the technician contain choices and recommen- collection (and the consent form, dations for preserving solid tissue, if needed) to the surgeon, or high- i. Prepare the tissue sample for and describe the roles of key peo- light on the operating list. snap-freezing on a clean sur- ple involved in the process. Consult ii. The surgeon should: face and using clean instruments; the CEN norms for more detailed a. complete the pathology form (if change instruments between pre- information on the processing of possible, in advance); paring normal tissue and tumour snap-frozen tissue and FFPE sam- b. perform the operative proce- tissue. The minimum volume of ples for protein DNA and RNA isola- dure and record the time of ar- tissue for snap-freezing is ap- tion (CEN/TS 16826-1–2 and CEN/ terial clamping and of excision proximately 0.5 cm3, although the TS 16827-1–3). of the specimen; and amount of tissue available will dif- c. place the specimen in a la- fer depending on the sample site. 4.2.1 Snap-freezing belled sterile pot or bag and Smaller fragments should still be put it on ice. snap-frozen and stored in the tis- Snap-freezing is the process by iii. The operating theatre staff should sue bank; if there is sufficient ma- which samples are lowered to tem- send the fresh tissue specimen terial, freeze duplicate samples. peratures below −70 °C very rapidly to the pathology department ii. Pre-cool the freezing medium using dry ice or LN2. This method immediately. isopentane (2-methylbutane) until can provide excellent sample integ- opaque drops begin to appear in rity and a wide array of options for 4.2.1.4 Histopathology the isopentane and the solution tissue analysis, including extraction department becomes misty; this will bring the of proteins, RNA, and DNA for use isopentane towards its freezing in research diagnosis. Before tissues i. Notify the pathologist and the tis- point (−160 °C), the optimal freez- are stabilized by freezing, the protein, sue bank research technician (if ing point for the tissue. Options:
RNA, and DNA profiles can change, not already present). a. LN2: suspend a vessel of iso- and these changes depend on the ii. Check the paperwork and allo- pentane in LN2. duration of warm and cold ischaemia cate a pathology number to the b. Dry ice: add dry ice (cardice) to and the ambient temperature before specimen as routine. the isopentane until a slush is
58 formed, or suspend a vessel of b. Orientate the tissue on a 4.2.3 Storage of FFPE blocks isopentane in dry ice. piece of cork and an equally and slides iii. Label cryovials, cryomoulds, or sized piece of Whatman paper cryostraws with a barcode and/ soaked in physiological salt i. FFPE blocks and sections mount- or sequential code (depending on solution. ed on slides can be stored at room local laboratory practice). Use a c. If the cryostraw system is used temperature. Prevent exposure of waterproof pen with ink that is to introduce a carrot of tissue blocks to sun or extreme temper- able to withstand long-term stor- into the straw, thermally seal ature variation or humidity. age at low temperatures. The each extremity and place in ii. Store blocks in moisture-resistant
sequential code is the local in- LN2. cardboard boxes or plastic stor- ventory code and must not relate age boxes. to the pathology number or other 4.2.2 Storage of tissue iii. Transfer details to the computer- identifiers. If a barcode is used, ized database system. readable recognition must also Storage of tissue can be done ac- iv. Update the database when sam- be included to make the sample cording to different protocols accord- ples are moved or depleted. identifier readable at institutions ing to the equipment available in the where there are no barcode facility. Options for storage: 4.2.4 Formalin fixation readers. i. Transfer the snap-frozen sam- iv. Record the local sequential code, ple from the isopentane to a Formalin fixation is standard practice the pathology number, the date, pre-chilled storage container for in most routine histopathology labo- the lag time from arterial clamp- transfer to either a locked −80 °C ratories. The following guidelines
ing and excision to freezing, freezer or a LN2 storage facility address specific issues related to and the type of tissue (the site, in the liquid or vapour phase. For preservation of formalin-fixed spec- and also whether the sample is storage for longer than 5 years, imens in biobanks. Table 6 provides
tumour, normal, and/or pre-ma- LN2 in the liquid or vapour phase information on the composition of lignant) in the inventory book. If is recommended. neutral buffered formalin. a barcode system is in use, the ii. Place cryostraws in a designat- i. Tissue specimens should not be barcode can be scanned into the ed visotube within a goblet (re- bigger than 3 cm × 2 cm × 0.5 cm.
LIMS and the above-mentioned movable LN2 storage elements) ii. Specimens should be fixed in
data recorded. and place in the locked LN2 fresh 10% neutral buffered for- v. Freeze directly in isopentane. Do repository. malin for a minimum of 4 hours not remove the tissue from the a. Store duplicate samples in a and a maximum of 48 hours, after isopentane until freezing is com- different storage facility if this which they should be embedded plete (5 seconds or less, depend- is available. in paraffin in accordance with ing on size), but ensure that the b. Check the backup system for conventional techniques. sample does not crack. Remove the storage repository – either iii. All reagents should be DNase- the sample from the isopentane a backup freezer running con- and RNase-free (e.g. prepared us- and enclose it in the labelled cryo- stantly or adequate supplies ing diethylpyrocarbonate [DEPC]
vial. It is good practice to strive of LN2. water). to snap-freeze all tissue within c. Record the storage details iv. Fixation media, such as Bouin’s 30 minutes of excision from the in the inventory system, and solution, that contain picric acid patient. Tissue subject to a delay check earlier data that were should be avoided, because this of up to 2 hours should still be col- entered. At a minimum, the compound interferes with subse- lected and the delay noted with- information recorded will in- quent PCR analysis of extracted in the local inventory database. clude the inventory number nucleic acids. Options for freezing: (local sequential code), the v. Alcohol fixation may be used as a. Embed the tissue samples in location, the pathology num- an alternative to formalin fixation. OCT compound and freeze in ber, the type of tissue (the site, For this, tissue is placed into 70% isopentane, or freeze directly and also whether the sample alcohol (diluted with DEPC water) in isopentane. The isopen- is tumour, unaffected/normal, for a minimum of 4 hours. tane used is cooled either by and/or pre-malignant), the lag Because of the chemical hazards SECTION 4 SECTION suspension in LN2 or through time between excision and of formalin, it can be desirable to use addition of dry ice. freezing, and the date. alternatives to formalin as a routine
Section 4. Selected protocols 59 Table 6. Composition of neutral buffered formalin and 70% ethanol
Composition Total volume
10% neutral buffered formalin (in 40% formaldehyde) 100 mL
100% formaldehyde 37–40 mL
Na2HPO4 (anhydrous) 6.5 g
NaH2PO4 4.0 g
Distilled water 900 mL
70% ethanol
100% absolute alcohol 70 mL of absolute alcohol + 30 mL of water 100 mL
96% ethanol 73 mL of 96% ethanol + 27 mL of water 100 mL
fixative. However, the effect of long- tion, simply remove the tissue from protocol, problems, or issues re- term storage with these alternative RNAlater and process. lated to the collection and storage. fixatives on the desired macromole- cules is not always known and should 4.2.6 Shipment of tissues and 4.3 Processing of urine and be established empirically. slides buccal cells
4.2.5 RNAlater FFPE tissues and slides are shipped The following protocols for process- at ambient temperature in accor- ing of urine and buccal cells contain This substance protects RNA in fresh dance with the established shipment recommended procedures. specimens. It eliminates the need guidelines and protocols of the send- to immediately process or freeze ing and recipient institutions. Please 4.3.1 Urine samples. refer to Section 3.9 for more details. i. Plastic or glass containers for 4.2.5.1 Tissue 4.2.7 Quality control for tissue collection of urine should be samples clean and dry, should have a 50– Cut the tissue to be smaller than 3000 mL capacity, a wide mouth, 0.5 cm in at least one dimension, i. Ensure that the reagents have and a leakproof cap, and should and then submerge the tissue in 5 vol- not expired and are of the correct be clearly labelled. umes of RNAlater (e.g. a 0.5 g sample composition and volumes. ii. When in transit, urine collections requires about 2.5 mL of RNAlater). ii. Keep high-quality records on all should be maintained on ice or variables related to specimens, refrigerated. 4.2.5.2 Cells FFPE tissues, and slides, includ- iii. Urine should be aliquoted accord- ing the time of tissue collection, ing to the volume needed for anal- Resuspend the pelleted cells in a the processing time, and the pe- ysis or storage. small volume of phosphate-buffered riod of storage before shipment iv. Depending on the analyte to be saline (PBS) before adding 5–10 and/or use. measured, a preservative may be volumes of RNAlater. added during collection or before 4.2.8 Data to be recorded aliquoting.
4.2.5.3 Storage v. Store urine at −80 °C or below in LN2. i. Date and time of tissue collection. RNAlater-treated tissue and cell sam- ii. Number of unprocessed samples, 4.3.2 Buccal cells ples can be stored at 4 °C for 1 month, FFPE blocks, and slides prepared. at 25 °C for 1 week, or at −20 °C for iii. Date and time of shipping. i. A collection kit (containing mouth- an indefinite period. For RNA isola- iv. Any variations or deviations from the wash, a 50 mL plastic tube, a
60 plastic biohazard bottle, and saliva proteome. The protocol for col- should be swabbed with a moist- courier packaging) is mailed or lection and processing of saliva is de- ened cotton applicator onto the given to the participant, along rived from the consortium’s Salivary lateral dorsum of the tongue to with an instruction sheet. The par- Proteome Handbook Procedures and stimulate the secretion. Aim to ticipant is to brush their teeth as Protocols (Hu et al., 2007). collect at least 200 μL of subman- usual, rinse their mouth out well i. Saliva collection should be done dibular saliva. with water twice, and then wait 2 in the morning (aim for 10:00– v. For the collection of sublingual hours. The participant should not 11:00 am if possible). Ask the saliva, the protocol is similar to eat or drink anything other than subject to refrain from eating, that described above for collec- water during this time. drinking, or oral hygiene proce- tion of submandibular saliva. The ii. After 2 hours, 10 mL of commer- dures for at least 1 hour before only difference is that the duc- cial mouthwash should be poured the collection. tal orifices of the submandibular into the tube, and then 10 mL of ii. The subject should be given gland are blocked off. Aim to col- tap water should be added. This drinking water (bottled) and asked lect > 100 μL of sublingual saliva diluted mouthwash should be to rinse their mouth out well (with- every time. placed into the mouth (without out drinking the water). vi. For the collection of parotid saliva, swallowing) and swished around iii. Five minutes after this oral rinse, use a parotid cup to collect the sa- vigorously for 30 seconds. the subject should be asked to liva. Parotid cups may be placed iii. The mouthwash should then be spit whole saliva into a 50 mL ster- bilaterally if the clinical investiga- spat back into the plastic tube, and ile centrifuge tube. The subject tor so chooses. This will enable the tube should be sealed tightly. should refrain from talking. It is the simultaneous collection from iv. The sample should be sent back better for the subject to drop their each parotid gland. The citric acid to the biobank immediately for head down and let the saliva run stimulation should be performed processing, or stored at 4 °C un- naturally to the front of the mouth, as described above. Aim to col- til it is sent, but it should be sent hold this position for a while, and lect > 1 mL of parotid saliva. The within 24 hours. spit into the tube provided. The first 0.1 mL of parotid saliva col- v. When the sample arrives at the subject will spit into the collection lected should be discarded, to laboratory, transfer the mouth- tube about once a minute for up ensure that fresh parotid saliva wash to 15 mL conical test tubes. to 10 minutes. The goal for each is obtained. vi. Add 35 mL of Tris-EDTA to the whole saliva donation should be Note: The collected samples mouthwash sample and spin at about 5 mL. Require that the tube should be kept on ice at all times 450g for 5 minutes. be placed on ice while collecting before processing. vii. Decant the supernatant and dis- whole saliva. Remind the subject vii. For sample processing using pro- card. not to cough up mucus, so that teinase inhibitors, to each 100 μL viii. Wash the cells twice, each time saliva is collected, not phlegm. of saliva: with 45 mL of Tris-EDTA. iv. For the collection of subman- a. Add 0.2 μL of proteinase inhibi- ix. Resuspend the cell pellet in 50 μL dibular saliva, use 2 × 2-inch cot- tor cocktail from standard stock of Tris-EDTA and transfer to 2 mL ton gauze to block the opening solution (Sigma, P8340), and labelled cryovials. of each parotid duct. Dry up the invert gently. x. Store the sample at −80 °C or in floor of the mouth, and block the b. Add 0.3 μL of sodium ortho-
LN2. openings of the sublingual gland vanadate (Na3VO4) (Sigma, Note: Buccal cells can also be (both sides), and have the sub- S6508) from standard stock of collected with other means, such as ject raise their tongue slightly to 400 mM, and invert gently. brushes. elevate the opening to the sub- viii. Centrifuge the specimens at mandibular gland. Begin to collect 2600g for 15 minutes at 4 °C (if 4.4 Collection and processing submandibular saliva by using a you note that incomplete separa- of saliva sterilized Wolf device. A sterilized tion has occurred, increase the and disposable yellow tip (for pi- spin time to 20 minutes). Then: A research consortium at the Univer- pette P200) should be connect- a. Remove the supernatants from sity of California, Los Angeles was ed into the device and changed the samples and label them funded by the United States National after every collection. During the with the term “super”, which Institute of Dental and Craniofacial collection, at 2-minute intervals, stands for the supernatant 4 SECTION Research to investigate the human a few grains of citric acid powder phase of the saliva.
Section 4. Selected protocols 61 b. Taking care not to disturb the sampled, take a separate speci- the head from the centre of one pellet and keeping the pellet as men and smear it onto another ear to the centre of the other, is in the original tubes, label the slide. gather a lock of hair at least the original tubes as “pellet”. ii. Immediately fix each slide. Either thickness of a pencil, and tie it ix. Freeze the samples at −80 °C. use spray fixative, at a right an- together near the root end (near gle to, and at a distance of 20 cm the scalp) using a small string or 4.5 Processing of cervical from, the slide, or immerse the a rubber band. cells slide in a container of 95% eth- ii. Cut the hair as close to the scalp anol for at least 5 minutes. If the as possible without cutting the In a Pap smear test, a sample of slide is not fixed immediately, the scalp. cells is taken from the uterine cervix cells will dry and become mis- iii. Maintain the horizontal position of using a wooden spatula or a brush, shapen; it will then not be possi- the hairs in the bundle by wrap- smeared onto a slide, and examined ble to read the slide accurately ping the cut section in aluminium under a microscope for abnormal in the laboratory. foil or plastic wrap. cells (precancer or cancer). This iii. Gently close and remove the iv. Indicate the root end and the tip protocol is a selected protocol from speculum. end by marking the foil or plastic diverse collection procedures. iv. Place all used instruments in wrap with a permanent marker or Note the following: decontamination solution. with a paper label. Do not use i. It is best not to take a smear from tape on the hair itself. a woman who is actively men- 4.5.3 After taking the smear v. Place the specimen in a clean, struating or has symptoms of an dry, labelled paper envelope for acute infection. Slight bleeding is i. Label the frosted edge of each shipment to the laboratory. Note acceptable. slide carefully. whether bleaches, hair dye, or ii. Pregnancy is not an ideal time for ii. On the patient record, note and medications (e.g. selenium or a Pap smear, because it can give illustrate any features you have minoxidil) were used. misleading results. noted: visibility of the transforma- Please note that hair from oth- tion zone, inflammation, ulcers or er sources (pubic, axillary, beard, 4.5.1 Taking the sample of other lesions, or abnormal dis- moustache, chest, etc.) may also cells charge. Note whether other sam- be analysed if head hair is not ples were taken, for example Pap available. Insert the long tip of the spatula into smears of other areas, and if the the cervical os, and rotate the spatula woman has been referred else- 4.6.2 Nails through a full circle (360°). If the cer- where, note to whom and when. vical broom brush is used, place the A clean pair of nail clippers should tip of the brush into the cervical os, 4.6 Processing of hair and be used. To clean nail clippers thor- and rotate the brush gently through nails oughly, they should be rubbed with three 360° circles. alcohol swabs. Nails should be clean These protocols are recommended of all polish, dirt, and debris. Nail clip- 4.5.2 Taking the Pap smear for collecting hair or nail specimens. pings from each finger or toe should be collected and packaged sepa- i. Smear both sides of the spatu- 4.6.1 Hair rately in plastic bottles. Each bottle la (or the contents of the brush) should be labelled with the mass of onto the glass slide with one or Head hair may be collected as follows. the nail collected and its source (e.g. two careful swipes. If any abnor- i. Along an imaginary line drawn right index finger) (NMS Labs and malities are seen outside the area across the middle of the back of ExperTox).
62 References
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68 Disclosures of interests
Dr Joakim Dillner reports that his unit at the Karolinska Institutet benefited from research funding from Sanofi Pasteur MSD and from Merck in 2014.
Dr Jan-Eric Litton reports holding intellectual property rights to the biobank lexicon Minimum Information about Biobank Data Sharing (MIABIS).
Dr Kurt Zatloukal reports having received personal consultancy fees from AstraZeneca and Daiichi Sankyo, support for travel from GlaxoSmithKline, and support from Daiichi Sankyo, Qiagen, and Siemens as an R&D partner. Dr Zatloukal is a European Committee for Standardization (CEN)/International Organization for Standardization (ISO) Technical Committee member.
Disclosures of interests 101 102